Ether-esters of organic hydroxy diphenyl acetic acid and process for manufacture of same



Patented Mar. 2, 1948 ETllER Es'll lRs OF ORGANIC HYDROXY DI- PHENYL ACETIC ACID ANDJROCESS FOR MANUFACTURE OF I AlexanderLang Morrison and Marianne Kiinigstein, Welwyn Garden City, England, assignors to Hoffmann-La'ltoche Inc.,' Nutley, N. J., a corporation of New Jersey No Drawing. Application April 1, 1947, Serial No. 788,734. In Great Britain March 30, 1946 Section 1, Public Law 690, August 8, 194 a Y '18 Claims.- (01. 260,472)

This invention relates to ether-"esters derived from organic hydroxy acids, more particularly basic. ether-esters derived from organic hydroxy acids related to mandelic acid, which have valuable pharmaceutical properties, and the manufacture thereof.

It is known that basic esters of mandelic acid, basic esters of benzilic, acid, basic-esters. of diphenyl-acetic acid and basic thefs bf beflhhydrol have an anti-acetyl-choline or anti-histamine action on the organism.

We have now found that certain basic ethers of basic esters of organic hydroxy acids of the following general formula:

R 00011 j r a R'/ \OH where R is an aromatic group such asphenylor a substituted phenyl-group wherein; said substituent is inertto the reagents used and R' may be hydrogen, alkyl, aralkyl, aryl, alkaryl or a homocyclic group, have anti-acetyl-choline or anti-histamine activity or both. r According to the present invention-we provide a process for the manufacture of "basic ethers having the general formula:

R3 R oc'm),.1}I

wherein R is a phenyl or a substituted phenyl wherein the substituentsflareiinert to there; agents used, R.Lis. hydrogen,v alkyl, aralkyl, varyl or "a homocyclic group. (such "as. cycloh'exyl); R is dialkylaminoalkyl; R and R are identical or difierent lower alkyl groups or combined as a poly-methylene group,'and n' is an integer not greater than 4; in-which a dialkylaminoalkyl (including piperidinoalkylrhalideis reacted with an alkaliumetal derivative of an ester of c the general formula: a a n 4.

R III coor R ox wherein R and B have the values assigned to them above, X and Y are alternatively hydrogen or a dialkylamino-alkyl (including piperidlnoalkyl) group and tained. v I g r --Thus-in the caseof-mandelicacid' or a-Sllbstituted' derivatives thereof, it is found that the the desired compound (II) obnon-basic esters of these acids when etherified such that the hydrogen of the hydroxyl-gro'up is replaced by a basic residue of the kind mentioned, substances are obtained which have relatively high antagonistic properties towards. acetylcholi-ne andhistamine. Further, if v the ester grouping is hydrolysed off and replaced by a basic residue, anti-acetyl-choline and anti-histamine properties are retained or'enhanced.

e In thie preparation ofbasic esters of mandelic acids ore-substituted mandelic acids containing a basicether grouping; it is preferable first to prepare the basic ether by reacting an alkali metal derivative of the hydroxy alkyl ester with a dialkylaminoalkyl-halide, hydrolysing cfiz' the alkyl group with an alkali-metal hydroxide and then reacting the salt so formed with adialkylaminoalkyl-halide.

It will be understood that basic esters having basic ether groups made according to the present-invention may have identical or dififerent basic groupings. The alkali-metal derivatives may, for instance, be prepared by saponification of the neutral esters with alkali hydroxide and the like. Generally, itis not necessary to prepare, the free acid. The derivative need not be isolated, as the solution or suspension of the derivative can be efiectively used in the reaction with the dialkylaminoalkyl halide. g H

The reaction proceeds best in the presence of an: inert-solvent suchgas' benzene or its homologues;.;y;l;' a @Weuse dialkylaminoalkyl chlorides as the preferred; dialkylaminohalides although it will be understoodthat the; corresponding bromides and iodides mayj.1a-ls0 be "used yandpcomep Within the scope; of" the ID3181111011.; The preferred alkalim'etal: derivatives are the sodium :and potassium derivativesr 2 g. of the dimethylaminoethyl ether of ethyl under reflux for 6 hours.

benzilate were heated with a solution of 2 g. caustic potash in 2 ml. water and 25 ml. ethanol The alcohol was then distilled oif and the residue dissolved in water. The pH of this solution was adjusted to pH 8 by the addition of dilute hydrochloric acid and the water removed by heating under reduced pressure. The re'sidue was drie'd'by distillation with benzene which "was then removed by distilling it ofi. The residue which contained the potassium salt of the dimethylaminoethyl ether of benzilic acid was then reacted with an excess of freshly prepared p-chloroethyldiethylamine in 20 cc. benzene and the mixture refluxed for 60 minutes. After cooling, the reaction product is shaken with water and the benzene layer separated, and extracted with dilute hydrochloric acid. On making this acid extract alkaline with caustic soda solution, the basic ether separated as an oil. The oil was taken up in ether, the ethereal solution washed with water, dried over sodium sulfate and, after removal of the ether, the residue was distilled under reduced pressure. The pure p-dimethylaminoethyl ether of diethylaminoethyl benzilate was obtained, B. P. 168-170 Cjllismm.

aii'ieamp'le 2 A solution of 30 g. of the dimethylaminoethyl ether of "ethyl benzila't'e in'25'0 ccs. absolute alcohol was heated under reflux with a solution of 5,6 g. of sodium hydroxide in 6 cos. water for 1 hour. 'The'sodium salt of thedimethylam'inoethyl ether of 'benzili'cacid-separated rapidly from the reaction mixture and was finally filtered off, washed with absolute alcohol an'deth'er and dried. A suspension of 11.3 g. of this sodiumsalt in 55 ccsy'of dry toluene was treated with an excess of freshly prepared ,8-chloroe'thyldimethylamine (about 2 moles) and'heate'd under reflux with stirring for 3 hours. A further similar excess of ,o-"chloroethyldimethylamine wasa'dded'and heating under reflux continued "for a further two hours, The solid was filtered off and the filtrate worked up as described in the previous example yielding the p-d'imethylaminoethyl ether of p-dimethylaminoethylbenzilate as an oil of boiling point 188-190 C./0.7 mm.

Example 3 A similar toluene suspension of the sodium salt described in Example 2 was heated under reflux with stirring with a considerable excess of .freshly prepared N-(p-chloroethyl) -piperidine,a total of about 4 molecular proportions being added over a period of about 4 hours. The solid was filtered off and the'flltrate; 'on working up as already described, yielded p-dimethylaminoethyl ether of ,c-piperidinoethyl 'benzilate, an oil with Example 4 A suspension of "2516 g. of thepreviously described sodium salt in 128 cos. of dry toluene was heated withstirringunder reflux with one molecular proportion of freshly "prepared p-chloroethyldiethylamine for 1 hour. A further half molecular proportion of pchloroethyldiethylamine was added-and heating continued for a further hour. The'product was worked up as described above, yielding, as in Example 1, the p- 4 dimethylaminoethyl ether of ,B-diethylaminoethyl benzilate.

We claim: 1, Derivatives of [c-dimethylaminoethoxyl -diphenylacetic acid of the formula wherein X is selected from the group consisting of dimethylamino, diethylamino and piperidino radicals.

2, fi-Dimethylaminoethyl [,[i-dimethylaminoethoxy] -diphenylacetate.

'3. fl-Diethyla'minoethyl [,3-dimetnylaminoethoxy] -di-phenylacetate.

4. fl-N-Piperidinoethyl [p dimethylaminoethoxy] diphenylacetate.

5. Process for the manufacture of derivatives of [c-dimethylaminoethoxyl-diphenylacetic acid of the formula wherein X is selected from the group consisting of dimethylamino, diethylamino and piperidino radicals, comprising reacting an alkali metal salt of [c-dimethylaminoethoxyl-diphenylacetic acid with a compound selected from the group consisting of [3-dimethylamino-a-chloroethane, ,B-diethylamino-a-chloroetha'ne and c-N-piperidino-u. chloroethane.

6. Process for the manufacture of ,B-dimethylaminoethyl [fl-dimethylaminoethoxyl-diphenylacetate, comprising reacting the sodium salt of [p-dimethylaminoethyoxyl -dipheny1acetic old with B-dimethylamino-u-chloroethane.

7. Process for the manufacture of fidimethylaminoethyl [B-dimethylaminoethoxy]-dipheny1- acetate, comprising reacting the sodium salt of [,8-dimethylaminoethoxy] -diphenylacetic acid with B -diethylamino-a-chloroethane.

8. Process for the manufacture of p-N-pip'eri dinoethyl [c-dimethylaminoethoxy] -diphenylacetate, comprising reacting the sodium salt of [fi-dimethylaminoethoxy] -diphenylacetic acid with ,B-N-piperidino-a-chloroethane.

ALEXANDER LANG 'MORRISON. MARIANNE K'ONIGSTEIN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,987,546 Blankart Jan. 8, 1935 2,394,770 Hill 'et al. Feb. 12, 1946 FOREIGN PATENTS Number Country Date 185,361 Switzerland Oct. 1, 1946 OTHER REFERENCES Burtner et al., Journal of the American Chem. 800., Vol. 65, pages 262-267 (1943) 

